Bone Erosion In Rheumatoid Arthritis Research Articles

The correlation between interleukin-34 and bone erosion under ultrasound in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy characterized by excessive synovial hyperplasia and progressive joint destruction. Pro-inflammatory cytokines play major roles in the regulation of synovial inflammation. The contribution of interleukin-34 (IL-34) in RA pathogenesis has been strongly suggested in clinical studies.Aim: To investigate the correlation between plasma IL-34 and disease parameters in RA patients including disease activity score (DAS28), receptor activator of NF-B ligand (RANKL) concentration, synovitis and bone erosions under ultrasound.Methods: 60 RA patients and 20 healthy controls were from Huashan Hospital, patient's medical history, physical examination, laboratory examination and ultrasound data were collected and recorded, respectively. Blood samples of all participants were collected and the levels of IL-34 and RANKL were tested. The levels of IL-34 and RANKL in RA patients were compared with those of healthy controls. Furthermore, the correlation between IL-34, RANKL and disease parameters in RA patients was analyzed.Results: Both plasma levels of IL-34 and RANKL in RA patients were significantly higher than the healthy controls (p < .05). IL-34 was significantly related to disease activity scores (r = 0.43, p = .001); RANKL (r = 0.46, p = .0003) and bone erosions by ultrasound (r = 0.38, p = .002).Conclusions: The plasma IL-34 concentration in RA was significantly higher than the healthy controls and was significantly correlated with RANKL, as well as disease activity score and bone erosions by ultrasound. The IL-34 may be a new biological marker for disease activity and predictor for bone erosions in RA. Targeting IL-34 holds promise in the management of RA and, potentially, other osteoclasts driven diseases (erosive osteoarthritis and psoriatic arthritis for example).

Imaging in rheumatoid arthritis: the role of magnetic resonance imaging and computed tomography.

In suspected and diagnosed rheumatoid arthritis (RA), magnetic resonance imaging (MRI) allows detection of all relevant pathologies, such as synovitis, tenosynovitis, bone marrow edema (osteitis), bone erosion and cartilage damage. MRI is more sensitive than clinical examination for monitoring disease activity (i.e., inflammation) and more sensitive than conventional radiography and ultrasonography for monitoring joint destruction. In suspected RA, MRI bone marrow edema predicts development of RA, and in early RA patients, it predicts subsequent structural damage progression. CT is the standard reference imaging modality for visualizing bone damage, including bone erosions in RA, but lacks sensitivity for soft-tissue changes, including synovitis and tenosynovitis. CT has a minimal role in RA clinical trials and practice, except in selected patients where MRI is contraindicated or not available or if crystal arthritis such as gout or pseudo-gout is suspected. MRI has documented utility in diagnosis, monitoring and prognostication of patients with RA and is increasingly used for these purposes in clinical practice and particularly clinical trials.

Radiographic scoring methods in rheumatoid arthritis and psoriatic arthritis.

Structural changes of bone and cartilage are the hallmarks of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Radiography can help in making diagnosis and in differentiating PsA and RA from other articular diseases. Radiography is still considered the preferred imaging method to assess disease progression, reflecting cumulative damage over time. The presence of bone erosions in RA is as an indicator of irreversible articular damage. Radiographic features of PsA are characteristic and differ from those observed in RA, especially in the distribution of affected joints and in the presence of destructive changes and bone proliferation at the same time. Semiquantitative scoring methods are designed to measure the degree of radiographically detectable joint damage and of changes over time. Several radiographic scoring methods that had been developed originally for RA have been adopted for the use in PsA. This review discusses the use of conventional radiography for diagnosing and detecting early structural changes in RA and PsA and providing a historical overview of commonly used scoring methods.

Control of inflammatory bone destruction by targeting the Wnt signaling pathway.

Bone erosions develop early in the course of rheumatoid arthritis(RA)and are predictive of a worse prognosis. They deteriorate gradually and cause joint damage, resulting in impaired functional capacity and disability. Lately, a considerable number of studies have increased our understanding of the pathogenic mechanisms participating in the development of bone erosions in RA. Osteoclasts are responsible cells and multiple factors have been identified to stimulate their differentiation and function. RANKL(receptor activator of NF-κB ligand)and other cytokines have been known for a long time to enhance osteoclastogenesis, but the role of other pathways has also been revealed recently. Besides to excessive ostaoclastogenesis, impair osteoblast differentiation and function also plays part in bone erosion formation in RA. Inflamed synovial membrane products increased levels of cytokines and antagonists of the canonical Wnt signaling pathway, which inhibit osteoblast differentiation and function. It seems that downregulation of this pathway leads to impaired osteoblast differentiation and activity and consequently, to reduced capacity of bone erosion to repair. Preclinical studies show that these findings could have implications in RA treatment, although more studies are required in this direction.

A microfluidic chip-based co-culture of fibroblast-like synoviocytes with osteoblasts and osteoclasts to test bone erosion and drug evaluation.

Targeting fibroblast-like synoviocyte (FLS) migration and invasion-mediated bone erosion is a promising clinical strategy for the treatment of rheumatoid arthritis (RA). Drug sensitivity testing is fundamental to this scheme. We designed a microfluidic chip-based, cell co-cultured platform to mimic RA FLS-mediated bone erosion and perform drug-sensitive assay. Human synovium SW982 cells were cultured in the central channel and migrated to flow through matrigel-coated side channels towards cell culture chamber where RANKL-stimulated osteoclastic RAW264.7 and osteogenic medium (OS)-stimulated bone marrow mesenchymal stem cells (BMSC) were cultured in the microfluidic chip device, mimicking FLS migration and invasion-mediated bone erosion in RA. These SW982 cells showed different migration potentials to osteoclasts and BMSC. The migration of SW982 cells with high expression of cadherin-11 was more potent when SW982 cells were connected with the co-culture of RAW264.7 and BMSC. Simultaneously, in the co-cultured chamber, tartrate-resistant acid phosphatase (TRAP) activity of RANKL-stimulated RAW264.7 cells was enhanced, but alkaline phosphatase (ALP) activity was decreased in comparison with mono-cultured chamber. Furthermore, it was confirmed that celastrol, a positive drug for the treatment of RA, inhibited SW982 cell migration as well as TRAP activity in the cell-cultured microfluidic chips. Thus, the migration and invasion to bone-related cells was reconstituted on the microfluidic model. It may provide an effective anti-RA drug screen model for targeting FLS migration-mediated bone erosion.

Ferulic acid inhibits interleukin 17-dependent expression of nodal pathogenic mediators in fibroblast-like synoviocytes of rheumatoid arthritis.

Interleukin 17 (IL-17), a proinflammatory cytokine produced by T helper (Th) 17 cells, potentially controls fibroblast-like synoviocytes (FLS)-mediated disease activity of rheumatoid arthritis (RA) via IL-17/ IL-17 receptor type A (IL-17RA)/signal transducer and activator of transcription 3 (STAT-3) signaling cascade. This has suggested that targeting IL-17 signaling could serve as an important strategy to treat FLS-mediated RA progression. Ferulic acid (FA), a key polyphenol, attenuates the development of gouty arthritis and cancer through its anti-inflammatory effects, but its therapeutic efficiency on IL-17 signaling in FLS-mediated RA pathogenesis remains unknown. In the current study, FA markedly inhibited the IL-17-mediated expression of its specific transmembrane receptor IL-17RA in FLS isolated from adjuvant-induced arthritis (AA) rats. Importantly, FA dramatically suppressed the IL-17-mediated expression of toll-like receptor 3 (TLR-3), cysteine-rich angiogenic inducer 61 (Cyr61), IL-23, granulocyte-macrophage colony stimulating factor (GM-CSF) in AA-FLS via the inhibition of IL-17/IL-17RA/STAT-3 signaling cascade. In addition, FA significantly decreased the formation of osteoclast cells and bone resorption potential in a coculture system consisting of IL-17 treated AA-FLS and rat bone marrow derived monocytes/macrophages. Furthermore, FA remarkably inhibited the IL-17-mediated expression of receptor activator of nuclear factor κ-Β ligand(RANKL) and increased the expression of osteoprotegerin(OPG) in AA-FLS via the regulation of IL-17/IL-17RA/STAT-3 signaling cascade. The therapeutic efficiency of FA on IL-17 signaling was further confirmed by knockdown of IL-17RA using small interfering RNA or blocking of STAT-3 activation with S3I-201. The molecular docking analysis revealed that FA manifests significant ligand efficiency toward IL-17RA, STAT-3, IL-23, and RANKL proteins. This study provides new evidence that FA can be used as a potential therapeutic agent for inhibiting IL-17-mediated disease severity and bone erosion in RA.

Association of CD26/dipeptidyl peptidase IV mRNA level in peripheral blood mononuclear cells with disease activity and bone erosion in rheumatoid arthritis.

Dipeptidyl peptidase IV (DPP-IV, CD26) plays many roles in the pathogenesis of several autoimmune and inflammatory diseases. The current study evaluated the association of DPP-IV enzymatic activity and its gene expression with disease activity and bone erosion in rheumatoid arthritis. Blood samples were collected from 20 rheumatoid arthritis patients and 40 healthy volunteers. Patients were divided into four subgroups using DAS28 index. CD26 gene expression levels were analyzed in peripheral blood mononuclear cells by quantitative reverse transcription-polymerase chain reaction. Additionally, the enzymatic activity of this molecule in serum was determined using Gly-Pro-p-nitroanilide as substrate. Digital radiography was applied to obtain images for bone erosion assessment. No significant difference in serum DPP-IV activity level was seen between patients and controls (p = 0.140). However, patients exhibited an increase in CD26 mRNA expression (1.68 times) when compared to controls (p = 0.001). Moreover, a strong positive correlation between CD26 gene expression and DAS28 index as well as bone erosion in the hands was observed (r = 0.71, p = 0.002 and r = 0.61, p = 0.049, respectively). This study demonstrated that CD26 mRNA expression in rheumatoid arthritis patients is associated with disease activity and bone erosion, suggesting a potential role for this molecule in the immunopathology of rheumatoid arthritis and bone erosion.

MiR-145-5p Increases Osteoclast Numbers In Vitro and Aggravates Bone Erosion in Collagen-Induced Arthritis by Targeting Osteoprotegerin.

BackgroundOsteoprotegerin (OPG) inhibits bone resorption and binds with strong affinity to receptor activator of NF κB ligand (RANKL), thereby preventing RANKL from binding to its receptor RANK. Osteoclasts have documented effects on bone erosion of rheumatoid arthritis (RA). The aim of this study was to examine the role of miR-145-5p in the regulation of RA osteoclast differentiation and bone erosion.Material/MethodsExpression of microRNA-145-5p in human peripheral blood mononuclear cells (PBMC) and synovial tissue was assayed by real-time polymerase chain reaction (RT-PCR). OPG, RANK, and RANKL expression in RAW-264.7 cells was examined by RT-PCR and Western blot analysis. Osteoclast formation was detected by tartrate-resistant acid phosphatase (TRAP) staining. The effect of miR-145-5p on predicted target mRNAs was examined by luciferase reporter assays. Collagen-induced arthritis (CIA) was induced by injecting DBA/1 mice with bovine type II collagen (CII), and miR-145-5p agomir was administered by intravenous injection. Morphological changes in the CIA joint were assessed by micro-computed tomography (CT) and histopathology.ResultsmiR-145-5p levels significantly increased in RA PBMC and synovial tissue compared with normal PBMC and osteoarthritis (OA) tissue. After transfection of RAW-264.7 cells with miR-145-5p, RANK and RANKL expression increased significantly, while OPG expression decreased significantly. TRAP staining results showed osteoclast numbers increased. Micro-CT analysis of the arthritic joints showed that the miR-145-5p agomir caused bone erosion in mice, and histopathological analysis revealed that miR-145-5p agomir aggravates cartilage erosion.ConclusionsOur findings indicate that administration of miR-145-5p aggravates joint erosion in CIA mice. This suggests that miR-145-5p is a potential target for the treatment of RA.

Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation.

C-reactive protein (CRP) is an established marker of rheumatoid arthritis (RA) but with ill-defined actions in the pathogenesis. Here, we show that CRP regulates the differentiation of osteoclasts, a central mediator of joint inflammation and bone erosion in RA, in a conformation- and receptor activator of NF-κB ligand (RANKL)-dependent manner. CRP in the native conformation is ineffective, whereas the monomeric conformation (mCRP) actively modulates osteoclast differentiation through NF-κB and phospholipase C signaling. Moreover, mCRP can bind RANKL, the major driver of osteoclast differentiation, and abrogate its activities. The binding and inhibition of RANKL are mediated by the cholesterol binding sequence (CBS) of mCRP. Corroborating the in vitro results, CRP knockout exacerbates LPS-induced bone resorption in mice. These results suggest that mCRP may be protective in joint inflammation by inhibiting pathological osteoclast differentiation and that the CBS peptide could be exploited as a potential RANKL inhibitor.

Anti-citrullinated alpha enolase antibodies, interstitial lung disease and bone erosion in rheumatoid arthritis.

RA is an articular chronic inflammatory disease that in a subgroup of patients can also present with extra-articular manifestations (EAMs). Despite intense investigation on this topic, reliable biomarkers for EAMs are lacking. In recent years several ACPAs, including those targeting anti-citrullinated alpha enolase peptide-1 (anti-CEP-1), have been identified in patients with RA. Data about the ability of anti-CEP-1 to predict the development of erosive disease are confliciting and no evidence concerning their possible association with EAMs in RA is currently available. The aim of this study was to investigate the prevalence and significance of anti-CEP-1 with regard to the association with erosive disease and EAMs in a large cohort of patients with RA. Anti-CCP and anti-CEP-1 antibodies have been assessed on serum samples of RA patients, healthy donors and patients with SpA using commercially available ELISA kits. Anti-CEP-1 antibodies are detectable in over 40% of RA patients and are associated with erosive RA and with RA-associated interstitial lung disease (ILD). Anti-CEP-1 antibodies may represent a useful biomarker for RA-associated ILD and erosive disease to be employed in clinical practice.

Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue of rheumatoid arthritis

BackgroundWe have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA.MethodsThe serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin αvβ3 in the ankle joint tissues of the mice were examined by double immunofluorescence.ResultsOur results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin αvβ3, OPN functions as a mediator of AD and osteoclasts.ConclusionsOur study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment.

Secondary osteoporosis. Bone metabolic disorder in Rheumatoid arthritis.

Rheumatoid arthritis(RA)is an immune-mediated disease marked by chronic synovial inflammation, which leads to cartilage and bone destruction as well as systemic bone loss. Osteoporosis or the systemic bone loss associated with RA increases the risk for fragility fractures, which can affect quality of life dramatically in RA patients. Inflammatory cytokines such as TNF and IL-6 in inflamed synovium induce the differentiation of osteoclasts, while suppresses the differentiation of osteoblasts, resulting in imbalance in bone metabolism. Although RA treatment targeting inflammatory cytokines can deter the progression of cartilage and bone destruction directly or indirectly, it can not stop systemic osteoporosis. Although it is important to avoid immobility by introducing an early remission, it is necessary to thoroughly manage the risks of individuals of RA patients and to effectively use osteoporosis drugs such as anti-RANKL antibodies that also have the effect of suppressing bone erosion in RA.

Cone-beam computed tomography, a new low-dose three-dimensional imaging technique for assessment of bone erosions in rheumatoid arthritis: reliability assessment and comparison with conventional radiography – a BARFOT study

Objectives: To determine the intra- and inter-observer agreement of erosions detected and scored with cone-beam computed tomography (CBCT) of bones in the hands and feet, and to compare CBCT with conventional radiography (CR) for assessment of bone erosions in patients with long-standing rheumatoid arthritis (RA).Method: Thirty patients with long-standing RA from the Better Anti-Rheumatic PharmacOTherapy (BARFOT) cohort were examined with CBCT and CR of hands and feet at their 15 year follow-up. Intra- and inter-class correlation coefficients (ICCs) were calculated. Erosions were analysed with the total rheumatoid arthritis magnetic resonance imaging erosion score (RAMRIS erosion score) for ICCs with CBCT, and with the modified RAMRIS erosion score (RAMRIS-mod.) for the same locations as used in the Sharp van der Heijde score and Sharp van der Heijde erosion score for CR.Results: All 30 patients showed erosions on CBCT and 26 on CR. The ICCs for both intra- and inter-observer reliability were 0.92–0.99. CBCT showed numerically more erosions than CR for all regions compared, although a statistically significant difference was found only for the metacarpophalangeal joints [median number of eroded joints 1.0 (range 0–14) with CBCT and 0.5 (0–13) with CR, p = 0.044].Conclusion: CBCT has high reproducibility and is more sensitive than CR in detecting erosions in this cohort of patients with long-standing RA. CBCT has the potential to become an important tool in the detection and follow-up of erosions in patients with RA.

Automatic identification of bone erosions in rheumatoid arthritis from hand radiographs based on deep convolutional neural network

Although radiographic assessment of joint damage is essential in characterizing disease progression and prognosis in patients with rheumatoid arthritis (RA), it is often difficult even for trained radiologists to find radiographic changes on hand and foot radiographs because lesion changes are often subtle. This paper proposes a novel quantitative method for automatically detecting bone erosion on hand radiographs to assist radiologists. First, the proposed method performs with the crude segmentation of phalanges regions from hand radiograph and extracts the detailed phalanges regions by the multiscale gradient vector flow (MSGVF) Snakes method. Subsequently, the region of interest (ROI; 40ź?ź40 pixels) is automatically set on the contour line of the segmented phalanges by the MSVGF algorithm. Finally, these selected ROIs are identified by the presence or absence of bone erosion using a deep convolutional neural network classifier. This proposed method is applied to the hand radiographs of 30 cases with RA. The true-positive rate and the false-positive rate of the proposed method are 80.5% and 0.84%, respectively. The number of false-positive ROIs is 3.3 per case. We believe that the proposed method is useful for supporting radiologists in imaging diagnosis of RA.

Deduction of Novel Genes Potentially Involved in Osteoblasts of Rheumatoid Arthritis Using Next-Generation Sequencing and Bioinformatic Approaches.

The role of osteoblasts in peri-articular bone loss and bone erosion in rheumatoid arthritis (RA) has gained much attention, and microRNAs are hypothesized to play critical roles in the regulation of osteoblast function in RA. The aim of this study is to explore novel microRNAs differentially expressed in RA osteoblasts and to identify genes potentially involved in the dysregulated bone homeostasis in RA. RNAs were extracted from cultured normal and RA osteoblasts for sequencing. Using the next generation sequencing and bioinformatics approaches, we identified 35 differentially expressed microRNAs and 13 differentially expressed genes with potential microRNA–mRNA interactions in RA osteoblasts. The 13 candidate genes were involved mainly in cell–matrix adhesion, as classified by the Gene Ontology. Two genes of interest identified from RA osteoblasts, A-kinase anchoring protein 12 (AKAP12) and leucin rich repeat containing 15 (LRRC15), were found to express more consistently in the related RA synovial tissue arrays in the Gene Expression Omnibus database, with the predicted interactions with miR-183-5p and miR-146a-5p, respectively. The Ingenuity Pathway Analysis identified AKAP12 as one of the genes involved in protein kinase A signaling and the function of chemotaxis, interconnecting with molecules related to neovascularization. The findings indicate new candidate genes as the potential indicators in evaluating therapies targeting chemotaxis and neovascularization to control joint destruction in RA.

Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT).

The comparison between different techniques to quantify the 3-dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients. Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF. A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4mm3; mESE: 15.5 vs. 2.3mm3; manual = 7.2 vs. 1.52mm3; all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001). MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients.

Repair of Bone Erosion in Rheumatoid Arthritis by Denosumab: A High‐Resolution Peripheral Quantitative Computed Tomography Study

To compare the bone healing effects of denosumab and alendronate in female rheumatoid arthritis (RA) patients by high-resolution peripheral quantitative computed tomography. This is a post hoc analysis of a randomized controlled trial. Forty patients were randomized in a 1:1 ratio to receive either subcutaneous denosumab (60 mg) once or oral alendronate (70 mg) weekly for 6 months. The size of individual bone erosions and the presence and extent of erosion-associated sclerosis (marginal osteosclerosis) were measured in the second metacarpal head of the nondominant hand at baseline, 3 months, and 6 months. Forty-two erosions were identified at baseline. After 6 months, the width, depth, and volume of erosion significantly decreased in the denosumab group (-0.23 mm, -0.16 mm, -0.91 mm3 , respectively; all P < 0.01), whereas these parameters significantly increased in the alendronate group (0.19 mm, 0.32 mm, and 1.38 mm3 , respectively; all P < 0.01; between-group differences, P < 0.01 for all). Quantitative analysis showed that the bone mineral density of the erosion margin significantly increased only after treatment by denosumab (19.75 mg/cm3 ; P < 0.05 for denosumab, and -5.44 mg/cm3 ; P = 0.51 for alendronate; P < 0.05 for between-group differences). Inhibition of receptor activator of NF-κB ligand by denosumab can induce partial repair of erosions in patients with RA, while erosions continued to progress in patients treated with alendronate. Combining denosumab with disease-modifying antirheumatic drugs may be considered for RA patients with progressive bone erosions.

Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis

Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction.

SNX10 Plays a Critical Role in MMP9 Secretion via JNK-p38-ERK Signaling Pathway.

Matrix metalloproteinases (MMPs) plays a critical role in the degradation of extracellular matrix (ECM). Sorting nexin (SNX) 10 is a member of the SNX family, which functions in regulation of endosomal sorting and osteoclast activation, has been implicated to play an important role in the bone erosion of rheumatoid arthritis. In this study, we aimed to investigate the possible role of SNX10 on MMP9 secretion and the potential mechanism. By immunostaining and co-immunoprecipitation, we found that SNX10 was extensively co-localized with MMP9, indicating that SNX10 might participate in MMP9 trafficking. After knocking down SNX10 via siRNA, the secretion and activity of MMP9 was significantly reduced, but the amount of protein was increased. By contraries, over-expression of SNX10 could increase the secretion and activity levels. Deficiency of SNX10 impaired the differentiation and bone resorption function of osteoclast, with a low activity of MMP9 compared to WT one. In SNX10 knockout osteoclast, the phosphorylation levels of JNK, p38, and ERK were obviously down-regulated. Our results first identified the role of SNX10 in MMP9 trafficking and secretion, and provided an evidence for SNX10 as a possible therapeutic target for bone destructing disease. J. Cell. Biochem. 118: 4664-4671, 2017. © 2017 Wiley Periodicals, Inc.

Association of CD8+ T-cells with bone erosion in patients with rheumatoid arthritis.

Bone erosion is a major problem worsening quality of rheumatoid arthritis (RA) patients' lives. However, causal factors responsible for bone erosion in RA have remained unclear. We aimed to examine genetic variants conferring bone erosion in RA using a Korean genome-wide association study (GWAS) and to search for possible biological mechanisms underlying the development of bone erosion. We obtained genome-wide single nucleotide polymorphism (SNP) data for 711 Korean RA patients using Illumina HapMap 550v3/660W arrays. Associations between SNPs and bone erosion status based on the Steinbrocker staging system were examined using multivariate logistic regression. Cell-type-specific enrichment of the epigenomic chromatin annotation H3K4me3 at the bone erosion associated variants was further investigated using National Institute of Health Roadmap Epigenomics data. As we tested the associations between 439 289 SNPs and bone erosion in 385 patients with erosive RA and 326 with non-erosive RA, none of the tested SNPs reached the genome-wide significance threshold, although many loci showed modest genetic effect on bone erosion status with suggestive association (e.g., rs2741200 [P = 3.75 × 10-6 ] in the SLA-TG locus and rs12422918 [P = 4.13 × 10-6 ] in SRGAP1). However, the top-ranked SNPs and their linked proxies, which were mostly located in non-coding variants, were significantly co-localized with the highly tissue-specific regulatory marker H3K4me3 in CD8+ memory T-cells (P = 0.014). Although, there was no large-effect variants associated with bone erosion in our GWAS, we have shown that CD8+ memory T-cells may have relevance with bone erosion in patients with RA through the analysis of ChiP-seq data.